All category A, B, and D studies conducted on or as part of the CRU must adhere to the IRB and CRU approved Data and Safety Monitoring Plan (DSMP). Investigators should direct DSMP development questions to the JHBMC-CRU Research Subject Advocate at 410-550-1850.

The two required elements of DSMPs are the safety review plan and the plan for adverse event reporting. Questions regarding the DSMP will be asked in the CRU application

The DSMP should include the following components, when applicable.

• Statements that IRB approval will be obtained and copies of the approval letter, informed consent document and protocol/study procedures will be on file with the sponsor and CRU.
• Description of consenting process.
• Acknowledgement that all consent and study procedure changes will be submitted to the IRB.
• Safety tests that screen out ineligible subjects and those that monitor for toxicity and adverse outcomes. Include frequency of these tests. (IRB requirement)
• Confidentiality of data.
• Adverse event grading and attribution scales for classification of all adverse events. (NCRR and IRB requirement)

Standard definitions:

Definition of adverse event (AE): any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporarily associated with the use of a medical treatment or procedure regardless of whether it is considered related to the medical treatment or procedure

Definition of serious adverse event (SAE): any event that is fatal or life-threatening, that is permanently disabling, requires or extends hospitalization of the subject, represents a significant overdose or breach of protocol, or suggests that a drug, device, or procedure used in a research protocol has produced a congenital anomaly or cancer, or in the opinion of the investigator, represents other significant hazards or potentially serious harm to the research subject or others

Severity grading scale (Hopkins and WIRB defined)

Mild - (adverse event of little clinical significance)

Moderate - (adverse event between mild and severe causing some limitation of usual activities)

Severe/Serious - (an event that results in death, is life-threatening, requires or prolongs hospitalization, causes persistent or significant disability/incapacity, represents a significant overdose or breach of protocol, results in
congenital anomalies/birth defects or produces cancer, or in the opinion of the investigator, represents other significant hazards or potentially serious harm to the research subject or others)

Attribution scale (Hopkins and WIRB defined)

Not related - (clearly NOT related to the study)

Possible - (may be related to the study)

Probable - (likely related to the study)

Definite - (clearly related to the study)

Unable to assess

• To whom, and with what frequency, unexpected adverse events and serious adverse events will be monitored and reported (NCRR and IRB requirement)
• Entity that will perform aggregate analysis of the adverse events
• Interval at which adverse events will be reviewed. (NCRR requirement)
• Definition of specific endpoints to be monitored. All studies that involve a potential mortality must include survival as a safety endpoint. (IRB requirement)
• Description of stopping rules.(IRB requirement)
• Description of study monitoring plan to include entity, frequency, and specific items to be reviewed (NCRR and IRB requirement)
• For multicenter studies, describe the composition of the reviewing body, what role it will play, the frequency of meetings, and how reports will be disseminated and to whom. (Note: For multi-center studies, the IRB and CRU will accept DSMPs and Safety Reports from external review panels provided they satisfy the minimum requirements.)

Plan 1: Minimal Risk study, not a clinical trial

• The study is not a clinical trial. It does not test a drug, biologic, device or novel model of therapy.
• The principal investigator will serve as the data monitor for this study.
• The investigator will provide interim reports as required to the IRB, and the JHBMC-CRU RSA.
• Serious adverse events will be reported to the IRB and the JHBMC-CRU RSA according to established IRB guidelines.
• Adverse events will be reported to the IRB, and JHBMC-CRU RSA according to established IRB guidelines.
• The JHBMC-CRU RSA will summarize serious events at regular intervals for review by the GAC. The frequency of serious adverse events will be monitored at appropriate intervals by the RSA in collaboration with the CRU Biostatistician.

Plan 2: Minimal risk study

• This may test an approved drug with a well-known adverse event profile, and include physiologic measurements that carry little risk to the participant or blood sampling.
• The principal investigator will serve as the data monitor for this study.
• The investigator will provide interim reports as required to the IRB, and the JHBMC-CRU RSA.
• Serious adverse events will be reported to the IRB and the JHBMC-CRU RSA according to established IRB guidelines.
• Adverse events will be reported to the IRB, and JHBMC-CRU RSA according to established IRB guidelines.
• The JHBMC-RSA RSA will summarize serious events at regular intervals for review by the GAC. The frequency of serious adverse events will be monitored at appropriate intervals by the RSA in collaboration with the CRU Biostatistician.

Plan 3: More than minimal risk study

• The principal investigator may serve as the monitor if the study is appropriate (e.g. physiologic testing that includes measurements that carry more than minimal risk to participant). If the risk to the study exceeds this, an external monitor or Data Safety Monitoring Board will be appointed for the study and has no conflict of interest as defined by the JHU Conflict of Interest Committee.
• The investigator will provide interim reports as required to the IRB, and the JHBMC-CRU RSA.
• Serious adverse events will be reported to the IRB and the JHBMC-CRU RSA according to established IRB guidelines.
• Adverse events will be reported to the IRB, sponsor, the JHBMC-CRU RSA, and the FDA (if indicated) according to established IRB guidelines.
• The Principal Investigator will provide the monitor (or Data Safety Monitoring Board) and the JHBMC-CRU RSA a tabulation of the number of subjects enrolled, number of specific adverse events (defined as any medical occurrence in a subject regardless of causal relationship with the study, as determined by the investigator) and a summary of the study at regular intervals.
• The frequency of these reports will vary depending on rate of enrollment of subjects. Subject confidentiality and the randomization of subjects will be preserved.
• The GAC and IRB will receive interim reports at regular intervals.
• The frequency of serious adverse events and adverse events will be monitored at appropriate intervals by the RSA in collaboration with the CRU Biostatistican.

Plan 4: Large, Multicenter study

• The sponsor will appoint an independent Data and Safety Monitoring Board (DSMB) to monitor the accumulating data in this protocol.
• Thee will also be a separate steering committee. The steering committee usually consists of a chairman, a set of investigators representing the clinical centers, the clinical monitor and a statistician. The steering committee provides overall scientific and operational direction for the trial through consideration of recommendations from other working committees. The steering committee has the ultimate responsibility for deciding whether the recommendations of the DSMB should be implemented.
• The DSMB is responsible for monitoring study progress, outcomes, and safety and to make recommendations tin regard to protocol changes. The DSMB approves the procedures used to monitor the study, for consideration of early stoppage of any of its components and will make recommendations when appropriate based on the regular review of all pertinent study data, including adverse effects and unblended outcome data.
• The coordinating center will provide study data for review by the DSMB. The DSMB will report its recommendations to the Principal Investigaor. This will be forwarded to the IRB and JHBMC-CRU RSA.
• Serious adverse events will be reported to the IRB and the JHBMC-CRU RSA according to established IRB guidelines. Adverse events will be reported to the IRB, sponsor, the JHBMC-CRU RSA, and the FDA (if indicated) according to established IRB guidelines.
• The frequency of serious adverse events and adverse events will be monitored at appropriate intervals by the RSA in collaboration with the CRU Biostatistician.
• The GAC and IRB will receive interim reports at regular intervals.

Plan 5: High risk protocols or protocols involving at-risk populations

The protocol may include a potentially high-risk intervention, drug or device. This would include gene therapy. Alternatively the subject population may be considered high risk (e.g. subjects who cannot provide informed consent, such as people with dementia, children, and subjects who are art risk of excessive coercion). The JHBMC-CRU RSA will provide ongoing audit of consent, and collection of data, and provide ongoing review of adverse event reporting in this group.

Please provide the CRU with the name and contact information for the following:

• Person who will conduct protocol compliance checks and data accuracy reviews.
• Primary contact for adverse event reporting and Data and Safety Monitoring Reports (DSMRs)